Many nervous system injuries sever distal axons, but leave proximal neuronal cell bodies intact. Recovery of function is largely dependent on the degree of axonal regeneration. After CNS damage, as occurs in spinal cord injury, axonal regeneration is routinely dismal. Nogo was recently identified as a CNS myelin-derived inhibitor of axonal regeneration. An understanding of the mechanism of Nogo action is critical to assessing and modulating its physiologic role. Here, we seek to characterize a Nogo receptor and to define its physiologic role. In preliminary studies, we have characterized a high affinity Nogo-66 binding site and obtained functional evidence that a novel brain-specific leucine-rich repeat protein mediates Nogo action. In the first specific aim, we will characterize this receptor protein by determining structure-function relationships for Nogo binding and axon repulsion, and by analyzing expression patterns before and after neural trauma. The absence of an intracellular signaling domain in this receptor protein implies an interaction with a second transmembrane receptor subunit responsible for transduction.
The second aim i s to identify this additional receptor subunit through its affinity for the identified Nogo binding receptor protein and by analyzing Nogo-induced tyrosine phosphorylation. Thirdly, a strain of mice lacking the Nogo receptor protein will be generated by homologous recombination. Neuronal development and the degree of anatomical recovery after neuronal trauma in these mice will be characterized. The identification of Nogo and its receptor provides the opportunity for novel and rational therapeutic interventions in spinal cord injury. This research may also prove applicable to a wide range of chronic brain axonal injuries, such as traumatic brain injury, white matter strokes and chronic progressive multiple sclerosis.
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